This is an amended competitive continuation grant of the Udall Parkinson's Disease Research Center of Excellence at Harvard University and McLean Hospital, which is directed by Professor Ole Isacson. The Center performs scientific work on conceptually novel therapeutic approaches for Parkinson's disease organized around 2 Cores that serve this and other NIH PD Centers, and 3 specific Projects that explore the shared theme of "Novel Therapeutic Approaches for Parkinson's Disease" as outlined in PA 03-004. The first project examines functional differences between dopamine (DA) neurons in the substantia nigra (A9) that are vulnerable to PD compared to those spared in the same midbrain tissue region A10 (VTA). We discovered new gene and molecular candidates for neuroprotection by specific laser capture and genomic analysis of characteristic DA neurons, now tested systematically by tissue culture and animal models to identify new pathways and substances providing insights to the pathogeneses and novel therapies for PD. This project links to NIH Udall Centers, including specific collaborations with Duke U Udall Center for genomic convergence analysis of PD susceptibility genes from bioinformatics, linkage analysis and finally functional tests in our PD model systems. The second project derives post mitotic but immature DA neurons from primate and human stem cells for restorative transplantation into sophisticated PD model primates (including functional tests and imaging). This project works with collaborators and NIH Udall Centers, and is internally served by the Core, and specifically by its transplantation in PD primate models linked to the supply of genetically engineered human stem cells produced in the third project. In the third project (stem and neural cell biology), specific midbrain genes and transcription factors controlling DA neuron development (A9 and/or A10) are identified and engineered into mouse and human stem cells. The resulting DA neurons are tested for functional repair in PD models. By using combinations of factors, a large fraction of stem cell derived cultured TH-positive GFP labeled and DA A9 midbrain mouse or human neurons are sorted for purity and safety by the Center's advanced FACS technology before transplantation. This PD Center also provides significant PD research education and training for scientists, and service to the PD patient and medical research communities. This Center's 3 research projects and its integrated Administrative Core and a Clinical Transplantation, Bioinformatics, Human and Stem Cell Marker Core are unique components in the NIH Udall Center of Excellence Consortium. The Harvard-McLean NIH Parkinson's Disease Research Center of Excellence provides a specialized environment for synergistic PD research on stem cell derived therapies, novel insights into functional genetic analysis of vulnerability of midbrain DA neurons and cutting edge research of new modalities leading to novel treatments for PD patients.